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BACKGROUND: Given the high rates of mental health concerns and communication difficulties for adolescents a treatment intervention to allow for effective expression may be therapeutic. One of the leading writing practices is Pennebaker’s Expressive Writing (EW) intervention. EW involves individuals writing about their feelings and thoughts regarding negative life experiences. Benefits of EW include a reduction of psychological symptoms and doctor visits, and better adjustment. OBJECTIVE: To examine the role of using EW and creative writing as a group intervention for youth admitted to an inpatient psychiatric hospital (IPH) METHODS: The current study evaluated participant engagement in a 3-day EW activity facilitated by nurses and graduate students on the IPH unit under the supervision of the IPH unit nurse manager and course instructor. Participants included 23 youth between 12- and 18-years-old RESULTS: Of the 23 participants 49.69% discussed vivid descriptions of illness, 24.5% discussed negative emotions, 20.25% included casual explanation, 5.52% discussed polarized view, and 16.56% discussed their desires, wishes, and goals. The response rate of clinician’s review of the EW content included 58% of clinician’s coding was on the patient’s current state, 24% was on causal explanations, and 18% was on treatment options. CONCLUSION: The current EW intervention facilitated by nursing staff and graduate students in an IPH was found to be engaged in by participants and provide an additional therapeutic resource to participants. EW may foster patient communication with staff about their functioning, mental health concerns, and treatment needs.

Supplementary Table S1 from Identification of Aberrantly Methylated Genes in Association with Adult T-Cell Leukemia

The study aims to examine the impact of creative activities on adolescents, aged 12-18, hospitalized in an acute-care Inpatient Psychiatric Hospital (IPH) setting. While research on the health impact of creative writing has been discussed with adults, research on adolescents hospitalized in acute Inpatient Psychiatric Units (IPU) is limited. This study highlights how creative activities generate self-discovery and insights that are necessary for coping among adolescents in IPH. 70 creative writing and origami sessions were embedded as a part of group education from March, 2018 until Feb. 2020. A curriculum that considered the interests of current teenagers and the short length of stay (4-5 days) at the IPH was designed and delivered by a professional writer and their team consisted of health sciences students, medical students, and IPU nursing staff. After each session, a post-session survey was administered. The findings from 568 post-surveys suggest that the adolescents at the IPH expressed interest and engagement through creative activities. In addition, the findings suggest creative activities promote mood shifts, relaxation, and self-awareness, all critical for adolescents during a mental health crisis. Further studies are needed to assess if these activities lead to long-term coping strategies for participants following their hospitalization.

This text explores our work as Women of Color (WoC) nurturing spaces and practices in response to the mirage of support, the inadequacy of resources, and the tepid responses to systemic oppression within the diversity, equity, and inclusion efforts of our university, a Predominantly White Institution (PWI) in the Midwest. Via reflective vignettes, we discuss developing a community art collaboration as a counterspace, defined by various scholars as “social spaces ... which offer support and enhance feelings of belonging” (Ong, Smith, and Ko 2018, 207) for minoritized students. Throughout this text, we discuss the potential of art-based projects shaped by an anti-racist praxis as a resistance to the “check the box” institutional diversity efforts and as transformative spaces to imagine alternative academic futures for Women of Color staff, faculty, and students.

Background: Body mass index (BMI) is correlated with the outcomes of various metabolic and pathological conditions. To elucidate the factors affecting BMI in elderly persons, we studied elderly persons with and without diabetes mellitus for BMI management target values using receiver operating characteristic (ROC) analysis. Methods: We conducted a dietary survey targeting 60 elderly outpatients with type 2 diabetes mellitus (diabetes group, 70.1 ± 7.8 years) and 66 elderly persons who participated in a health class offered by the municipality (health class group, 72.5 ± 5.7 years). Results: In the diabetes group, positive correlations were observed between BMI and several variables including blood glucose levels (all P < 0.05), whereas BMI had negative correlations with the third principal component (positive weight for oils and fats). In addition, BMI was negatively correlated with the intake of oils and fats. In the health class group, BMI was positively correlated (all P < 0.05) with grip strength/sixth principal component (positive weight for sweets)/condiments. An analysis of dietary patterns revealed that dietary factors correlated with BMI in each group. The cutoff value of BMI was suggested to be near the normal upper limit or slightly higher in the subject group. Conclusion: We considered that BMI management was useful as an indicator for maintaining grip and muscle strength in elderly persons and as an indicator for diabetes care management. From the present study, we may propose the utility of a careful dietary survey as one of the approaches for these aims. J Clin Med Res. 2019;11(8):563-571 doi: https://doi.org/10.14740/jocmr3893

The aim of this study is to investigate how vegetable and fruit intake trends affect the estimated glomerular filtration rate (eGFR) by analyzing therapeutic diet status in elderly type 2 diabetes mellitus patients. The study included 59 elderly patients with type 2 diabetes mellitus (mean age: 70.1±7.8 y) who had previously received therapeutic education for type 2 diabetes mellitus from a clinical team and were subsequently receiving outpatient treatment. Blood examination data were retrospectively collected from medical records and diet status was investigated using a simplified self-administered diet history questionnaire. Dietary patterns were extracted using principal component analysis, and the relationships with each blood examination data were investigated. Linear regression analysis was then used to examine the intake food groups related to eGFR. Energy intake was 27±9 kcal/kg. Overall, these results were in line with the Guidelines for the Treatment of Diabetes in Japan 2016. As a result of principal component analysis, seven dietary patterns were extracted, and the cumulative contribution ratio of the seven components was 74.0%. Among the dietary patterns, the 6th factor (positive weighting with fruit) for eGFR was a negative prognostic factor (p=0.010). Analysis of food group intake and eGFR indicated that green and yellow vegetables were positive prognostic factors, whereas fruits were negative prognostic factors (both p

Background: We have been conducting liver disease education classes regularly in our hospital for the purpose of providing health information to patients and their families. Methods: In order to evaluate the effectiveness of these classes, we conducted a questionnaire survey of patients and family members who attended the classes held three times in 2012. The cumulative total number of participants was 80 (49 patients, 26 family members, and five others). The classes focused on the following areas: 1) prevention of hepatic cancer; 2) treatment of hepatic cancer; 3) iron restriction diet for hepatitis C patients; and 4) importance of branched-chain amino acid preparations. Self-evaluation of knowledge in these areas was based on a four-point scale. Results: A comparison of knowledge levels between the patients and their family members revealed no statistically significant differences. Therefore, subsequent analyses were performed by combining the patients and their families into one group. The knowledge level of the participants increased with the number of class attendances; that is, the more often they attended, the more they accumulated knowledge (Kruskal-Wallis test: P < 0.0001; P = 0.0368; P = 0.0021; and P < 0.0001). In addition, the results of the questionnaire administered immediately before and after the education class showed significant improvement in the knowledge level for each area. Conclusion: The results of this study indicate the liver disease education class to be effective for improving the knowledge of patients and their families. The importance of repeated information provision was also demonstrated. J Clin Med Res. 2017;9(3):207-212 doi: https://doi.org/10.14740/jocmr2914w

Background & aims Neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer (PC) is potentially associated with various toxicities, which can lead to impaired nutritional status. Eicosapentaenoic acid (EPA) can reduce proinflammatory cytokines and positively influence cancer cachexia syndrome. The aim of this study is to clarify the utility of EPA enriched nutrition support during NACRT for PC. Methods We randomly assigned 62 patients with PC that received NACRT to either a nutrition intervention (NI) or a normal diet (ND). Patients in the NI group received 2 bottles/day (550 kcal/day) of an EPA-enriched nutrition supplement during NACRT. The primary endpoints were the before-to-after NACRT ratios (post/pre ratios) of skeletal muscle mass and psoas major muscle area (PMA). The secondary endpoints were the post/pre ratios of other nutritional parameters and treatment-related toxicities. Results Only 14 patients (45.2%) in the NI group consumed more than 50% of the EPA-enriched supplement provided. The post/pre ratio of skeletal muscle mass in the NI group (0.99 ± 0.060) was not significantly different from that of the ND group (0.96 ± 0.079, p = 0.102). However, patients that consumed ≥50% of the EPA-enriched supplement (the good intake group) had significantly higher skeletal muscle mass ratios than patients in the ND group (p = 0.042). The PMA ratio was significantly higher in the NI group (0.96 ± 0.081) than in the ND group (0.89 ± 0.072, p = 0.001). The NI and ND groups were not significantly different in other nutritional parameters or in NACRT-related toxicity. Conclusions We found that EPA-enriched intake could potentially improve the nutritional status of patients with PC that received NACRT, but it was difficult for many patients to drink, due to its disagreeable taste. University Hospital Medical Information Network (http://www.umin.ac.jp), registration number UMIN000033589, https://upload.umin.ac.jp/cgi-bin/ctr_e/ctr_view.cgi?recptno=R000038300.

To develop a novel type of cheese using Aspergillus oryzae, four strains (AHU 7139, AHU 7140, AHU 7141 and AHU 7146) were tested with respect to their extracellular protease production on solid-state media containing heatdenatured whey protein under various temperatures and pH levels. Proteolytic activity of the crude enzyme extracts was evaluated under acidic condition considering the circumstance of cheese ripening. Zymographic analysis revealed that several kinds of proteases were secreted, which were dependent on the strain, incubation temperature and initial pH value. Using three strains, six types of culture products were selected as adjunctive materials in combination with an incubation temperature of 15 or 20oC and an initial pH condition of 4.0 or 6.5. Gouda-type cheese curd was prepared, and the curd particle received 1% (w/w) of the culture product, followed by pressing, cooling, salting and ripening for 3 months at 11.5oC. An increase in water extractable nitrogen and free fatty acid was observed in some experimental cheeses, depending on the strain and culture history. In particular, incorporation of culture products from A. oryzae AHU 7139, incubated at pH 6.5 and 20oC affected these parameters. As a novel dairy technology, this study propose new insights into the potential use of A. oryzae for providing an enzyme cocktail to develop palatable cheese flavor when suitable strains and culture conditions offer products with an optimum balance of proteases and lipases.

The Escherichia coli ygjD gene is critical for the universal tRNA modification N 6 -threonylcarbamoyladenosine, together with two other essential genes, yeaZ and yjeE . This study showed that the transcription of the thr and ilv operons in ygjD mutants was increased through the inhibition of transcription attenuation and that dnaG transcription was reduced.

In adult T-cell leukemia (ATL) cells, a defective human T-cell leukemia virus type 1 (HTLV-1) provirus lacking the 5′ long terminal repeat (LTR), designated type 2 defective provirus, is frequently observed. To investigate the mechanism underlying the generation of the defective provirus, we sequenced HTLV-1 provirus integration sites from cases of ATL. In HTLV-1 proviruses retaining both LTRs, 6-bp repeat sequences were adjacent to the 5′ and 3′ LTRs. In 8 of 12 cases with type 2 defective provirus, 6-bp repeats were identified at both ends. In five of these cases, a short repeat was bound to CA dinucleotides of the pol and env genes at the 5′ end, suggesting that these type 2 defective proviruses were formed before integration. In four cases lacking the 6-bp repeat, short (6- to 26-bp) deletions in the host genome were identified, indicating that these defective proviruses were generated after integration. Quantification indicated frequencies of type 2 defective provirus of less than 3.9% for two carriers, which are much lower than those seen for ATL cases (27.8%). In type 2 defective proviruses, the second exons of the tax , rex , and p30 genes were frequently deleted, leaving Tax unable to activate NF-κB and CREB pathways. The HTLV-1 bZIP factor gene, located on the minus strand, is expressed in ATL cells with this defective provirus, and its coding sequences are intact, suggesting its significance in oncogenesis.

A 65-year-old man with diabetes mellitus reporting fever and urination disturbance on a flight from Bangkok back to Japan in July 2003 was admitted elsewhere for acute prostatitis. Despite intravenous antibiotics, his condition deteriorated. On admission to our hospital, he suffered from respiratory failure, with laboratory data showing disseminated intravascular coagulation (DIC). Computed tomography (CT) shows infiltrative and nodular shadows in both lung fields and low-density areas in the left kidney and prostate gland, consistent with pneumonia and abscesses in these organs. He also developed broad osteomyelitis in the right lower extremity with cellulitis and arthritis in the right hand, knee, and foot. Blood, urine, and joint fluid culture all yielded Burkholderia pseudomallei, so he was diagnosed with melioidosis. Treatment was started with meropenem and minocycline, then meropenem was changed to imipenem. His symptoms gradually improved after ciprofloxacin was added, so all intravenous antibiotics were discontinued and he underwent oral treatment with chloramphenicol, minocycline, and sulfamethoxazole/trimethoprim in September 2003. He developed fever again, however, and oral therapy was discontinued and intravenous antibiotics restarted. After resolution of fever, oral maintenance therapy was initiated again with levofloxacin and minocycline in October, and his condition remained stable. After discharge in April 2004, he has been followed up with no evidence of relapse. This is considered to be the seventh case of melioidosis reported in Japan. Our patient manifested multiple organ lesions with sepsis and DIC, and was difficult to treat, but clinical symptoms improved in long-term antibiotic administration. With travelers to Southeast Asia increasing, greater attention must be paid to imported infectious diseases, such as melioidosis.

Human T-cell leukemia virus type I (HTLV-I) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-I proviral integration site remains unsolved. We determined the integration sites of HTLV-I proviruses in ATL cells and HTLV-I–infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-I provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-I provirus was prone to integration near the transcriptional start sites in leukemic cells (P = .006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2/59; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I–infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.

In this study, we identified 53 aberrantly hypermethylated DNA sequences in adult T-cell leukemia (ATL) cells using methylated CpG island amplification/representational difference analysis method. We also observed a proportionate increase in the methylation density of these regions with disease progression. Seven genes, which were expressed in normal T cells, but suppressed in ATL cells, were identified near the hypermethylated regions. Among these silenced genes, Kruppel-like factor 4 (KLF4) gene is a cell cycle regulator and early growth response 3 (EGR3) gene is a critical transcriptional factor for induction of Fas ligand (FasL) expression. Treatment with 5-aza-2′-deoxycytidine resulted in the recovery of their transcription, indicating that their silencing might be associated with DNA hypermethylation. To study their functions in ATL cells, we transfected recombinant adenovirus vectors expressing KLF4 and EGR3 genes. Expression of KLF4 induced apoptosis of ATL cells whereas enforced expression of EGR3 induced the expression of FasL gene, resulting in apoptosis. Thus, suppressed expression of EGR3 enabled ATL cells to escape from activation-induced cell death mediated by FasL. Our results showed that the methylated CpG island amplification/representational difference analysis method allowed the isolation of hypermethylated DNA regions specific to leukemic cells and thus shed light on the roles of DNA methylation in leukemogenesis.

To clarify the status of tax gene, we analyzed human T-cell leukemia virus type-I (HTLV-I) associated cell lines and fresh adult T-cell leukemia (ATL) cells. We compared 2 types of HTLV-I associated cell lines: one was derived from leukemic cells (leukemic cell line) and the other from nonleukemic cells (nonleukemic cell line). Although all nonleukemic cell lines expressed Tax, it could not be detected in 3 of 5 leukemic cell lines, in which nonsense mutation or deletion (60 bp) of tax genes, and DNA methylation in 5'-LTR were identified as the responsible changes. We found such genetic changes of the tax gene in 5 of 47 fresh ATL cases (11%). The tax gene transcripts could be detected in 14 of 41 fresh ATL cases (34%) by RT-PCR. In ATL cases with genetic changes that could not produce Tax protein, the tax gene was frequently transcribed, suggesting that such cells do not need the transcriptional silencing. Although DNA methylation of 5'-LTR was detected in the fresh ATL cases (19 of 28 cases; 68%), the complete methylation associated with transcriptional silencing was observed only in 4 cases. Since partial methylation could not silence the transcription, and the tax gene transcription was not detected in 27 of 41 cases (66%), the epigenetic change(s) other than DNA methylation is considered to play an important role in the silencing.

To investigate the HIV-1 subtypes prevalent in the Republic of Congo, we isolated 28 HIV-1 strains from Congolese AIDS patients in 1996 and 1997, and analyzed them phylogenetically. Phylogenetic analysis based on part of the 5' tat-env (vpu) and env sequences revealed that only 13 (46.4%) of the 28 isolates belonged to the same subtype in the vpu tree as in the env tree; the remaining 15 (53.6%) strains showed discordant subtypes between vpu and env with 6 different profiles; that is, 1 A/A (vpu/env), 1 D/D, 5 G/G, 4 H/H, 2 unclassified (U)/U, 9 G/A, 2 G/H, 1 G/J, 1 H/G, 1 U/A, and 1 U/J. Thus, 9 of the 15 discordant HIV-1s were of the G/A (vpu/env) type, and did not form any subcluster within the subtype G lineage in the vpu-based phylogenetic tree. In addition, CRF02_AG (IbNG), which is a G/A (vpu/env) type, was not found in the Republic of Congo. These data suggest that the majority of HIV-1 subtypes circulating in the Republic of Congo have mosaic structures and may have been derived from independent recombinational events.

Reaction time (RT) is known to be longer for simultaneous bimanual responses than for unimanual ones. This phenomenon is called "bilateral deficit". To identify the mechanisms subserving the bilateral deficit, brain electrical activity was examined, with a source derivation method, in 12 right-handed subjects, during the preparation and execution periods of a RT task. The responses were either unilateral or bilateral index finger flexion, performed either in a simple RT condition, with 20% catch trials, or in a choice RT condition. A deficit was observed in RT for the bilateral response for the right-index finger movement. In cerebral electrical activities, no evidence of a correlate of a bilateral deficit was found during the preparatory period. Conversely, during the execution period, an EEG correlate of the bilateral deficit was found. For the right hand, the activation of the sensorimotor area directly involved in the voluntary control was weaker for bilateral than for unilateral contralateral responses. The reasons for such a bilateral command weakness are discussed in the context of our RT task. First, the constraint of synchronisation included in the bilateral response might require an interhemispheric information transmission that resulted in a braking effect. Second, given that an ipsilateral inhibition is present in case of choice between the two hands of one particular unimanual response, and given that this ipsilateral inhibition is also present in case of simple unimanual trials, we hypothesise that a mutual transcallosal inhibitory effect also persists in the bilateral response.

To assess the molecular epidemiology of HIV-1 in Republic of Congo (Congo), we investigated 29 HIV-1s obtained from 82 Congolese AIDS and ARC patients in 1996 and 1997. Part of the env region including the V3 loop was phylogenetically analyzed. The genotypes observed were varied: of 29 specimens, 12 (41 %) were subtype A, 1 (3%) was subtype D, 6 (21%) were subtype G, 6 (21%) were subtype H, 2 (7%) were subtype J, and 2 (7%) could not be classified as any known subtypes (U, unclassified). The heterogeneous profile of HIV-1 infection was different from the profiles of neighboring Central African countries. These data show that subtypes G and H as well as subtype A were circulating with high prevalence. The fact that new genetic subtypes (J and U) are circulating indicates a need for a greater surveillance for these subtypes both in Congo as well as in other parts of the world.

We analyzed 57 HIV-1 isolates from Cameroon and the Republic of Congo, with respect to the env C2V3 and/or the pol integrase regions. The results indicated that the topology of the pol tree correlated well with that of the env tree for four clusters of subtype D, F G and H, suggesting that these trees reflect the true evolution of the overall genome structures of these subtypes. However, of 22 Cameroonian isolates that were classified as subtype A based on env, 20 of them diverged in their pol sequence into two lineages that were completely different from the prototypical subtype A, tentatively designated as subtypes A1 and A2. The subtype A1 isolates (6 out of 22) were related in their env C2V3 regions with prototypical subtype A strain, but in their pol regions, they formed an independent cluster that diverged from known HIV-1 subtypes so far reported (except for subtypes I and J). The subtype A2 isolates (14 out of 22), which represent the major epidemic type of HIV-1 in Cameroon, clustered distinctly in both the env and pol trees with the recently described A/G mosaic strains from Nigeria and Djibouti. These two lineages were not spreading in the neighboring Republic of Congo.

Maximal voluntary strength of simultaneous bilateral exertion has been shown to be small compared to the sum of the unilateral exertions. Three experiments were conducted to determine the effects of bilateral and unilateral resistance training on this bilateral deficit and to compare these in hands, arms, and legs. In each experiment, the subjects were divided into three groups: unilateral training group, bilateral training group, and control group. The subjects of the training group performed maximal isometric handgrip training in experiment I, and maximal isokinetic arm and leg extension training in experiments II and III. In each experiment, the subjects of the training group continued one of these resistance training exercises three times a week, for 6 weeks. The increase in handgrip strength of the bilateral training group produced in the bilateral condition [5.1 (SEM 2.4)%, after 3 weeks, 6.4 (SEM 2.3) %, after 6 weeks] was significantly greater compared with the control group [-1.1 (SEM 1.0) %, after 3 weeks, -1.5 (SEM 1.1) %, after 6 weeks. The increase in leg extension power of the bilateral training group produced in the bilateral condition [16.1 (SEM 9.6) %, after 3 weeks, 24.1 (SEM 7.4) %, after 6 weeks] was significantly greater compared with the unilateral training group [-5.0 (SEM 3.4) %, after 3 weeks, -3.4 (SEM 4.2) %, after 6 weeks] and the control group [-4.3 (SEM 2.5) %, after 3 weeks, 1.5 (SEM 5.5) %, after 6 weeks]. The increase in handgrip strength of the unilateral training group produced in the unilateral condition [7.3 (SEM 1.7) %, after 3 weeks] was significantly greater compared with the control group [-0.9 (SEM 1.8) %, after 3 weeks]. The increase in arm extension power of the unilateral training group produced in the unilateral condition [7.2 (SEM 1.8) %, after 6 weeks] was significantly greater compared with the bilateral training group [-3.0 (SEM 2.3) %, after 6 weeks] and the control group [-2.1 (SEM 2.6) %, after 6 weeks]. Bilateral indexes (BI) were shifted in a positive direction by bilateral training and tended to shift in a negative direction by unilateral training. With regard to the magnitude of change in BI, there were no significant differences among handgrip, arm extension, and leg extension training. It is suggested that there is lateral specificity in resistance training and that there is no difference among body parts in the modification of bilateral deficit by lateral training.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia, a disease that is triggered after a long latency period. HTLV-1 is known to spread through cell-to-cell contact. In an attempt to study the events in early stages of HTLV-1 infection, we inoculated uninfected human peripheral blood mononuclear cells and the HTLV-1-producing cell line MT-2 into NOD-SCID, common γ-chain knockout mice (human PBMC-NOG mice). HTLV-1 infection was confirmed with the detection of proviral DNA in recovered samples. Both CD4 + and CD8 + T cells were found to harbor the provirus, although the latter population harbored provirus to a lesser extent. Proviral loads increased with time, and inverse PCR analysis revealed the oligoclonal proliferation of infected cells. Although tax gene transcription was suppressed in human PBMC-NOG mice, it increased after in vitro culture. This is similar to the phenotype of HTLV-1-infected cells isolated from HTLV-1 carriers. Furthermore, the reverse transcriptase inhibitors azidothymidine and tenofovir blocked primary infection in human PBMC-NOG mice. However, when tenofovir was administered 1 week after infection, the proviral loads did not differ from those of untreated mice, indicating that after initial infection, clonal proliferation of infected cells was predominant over de novo infection of previously uninfected cells. In this study, we demonstrated that the human PBMC-NOG mouse model should be a useful tool in studying the early stages of primary HTLV-1 infection.

Background Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period. Among accessory genes encoded by HTLV-I, the tax gene is thought to play a central role in oncogenesis. However, Tax expression is disrupted by several mechanims including genetic changes of the tax gene, deletion/hypermethylation of 5'-LTR. To clarify the role of epigenetic changes, we analyzed DNA methylation and histone modification in the whole HTLV-I provirus genome. Results The gag, pol and env genes of HTLV-I provirus were more methylated than pX region, whereas methylation of 5'-LTR was variable and 3'-LTR was not methylated at all. In ATL cell lines, complete DNA methylation of 5'-LTR was associated with transcriptional silencing of viral genes. HTLV-I provirus was more methylated in primary ATL cells than in carrier state, indicating the association with disease progression. In seroconvertors, DNA methylation was already observed in internal sequences of provirus just after seroconversion. Taken together, it is speculated that DNA methylation first occurs in the gag, pol and env regions and then extends in the 5' and 3' directions in vivo, and when 5'-LTR becomes methylated, viral transcription is silenced. Analysis of histone modification in the HTLV-I provirus showed that the methylated provirus was associated with hypoacetylation. However, the tax gene transcript could not be detected in fresh ATL cells regardless of hyperacetylated histone H3 in 5'-LTR. The transcription rapidly recovered after in vitro culture in such ATL cells. Conclusion These results showed that epigenetic changes of provirus facilitated ATL cells to evade host immune system by suppressing viral gene transcription. In addition, this study shows the presence of another reversible mechanism that suppresses the tax gene transcription without DNA methylation and hypoacetylated histone.

The IkappaB kinase (IKK)-related kinase NAK (also known as TBK or T2K) contributes to the activation of NF-kappaB-dependent gene expression. Here we identify NAP1 (for NAK-associated protein 1), a protein that interacts with NAK and its relative IKK epsilon (also known as IKKi). NAP1 activates NAK and facilitates its oligomerization. Interestingly, the NAK-NAP1 complex itself effectively phosphorylated serine 536 of the p65/RelA subunit of NF-kappaB, and this activity was stimulated by tumor necrosis factor alpha (TNF-alpha). Overexpression of NAP1 specifically enhanced cytokine induction of an NF-kappaB-dependent, but not an AP-1-dependent, reporter. Depletion of NAP1 reduced NF-kappaB-dependent reporter gene expression and sensitized cells to TNF-alpha-induced apoptosis. These results define NAP1 as an activator of IKK-related kinases and suggest that the NAK-NAP1 complex may protect cells from TNF-alpha-induced apoptosis by promoting NF-kappaB activation.

We found a novel primate lentivirus in mandrill (Mandrillus sphinx). To clarify the evolutionary relationships and transmission patterns of human/simian immunodeficiency virus (HIV/SIV), we screened blood samples from 30 wild-born healthy Cameroonian mandrills. Five (16.7%) of them were seropositive for SIV. Three SIV strains were isolated from the five seropositive mandrills by cocultivation of their peripheral blood mononuclear cells (PBMCs) with PBMCs of rhesus macaques, a human T cell line (M8166), and/or a cynomolgus macaque T cell line (HSC-F). One of the newly isolated SIV strains was intravenously inoculated into two rhesus macaques and resulted in chronic infection. In the SIV-infected macaques at 45 weeks after inoculation, we observed a mild decline in the number of peripheral CD4(+) lymphocytes, lymphadenopathy, and blastic follicular dendritic cells with mild follicular hyperplasia in the peripheral lymph nodes. A phylogenetic analysis based on the pol sequence showed that the newly found SIVs from Cameroonian mandrills did not cluster with SIVmndGB1, which is the former representative strain of SIVmnd. The SIVmnds from Cameroon formed a new, independent lineage that branched before the root of the HIV-1/SIVcpz lineage with 996 of 1000 bootstrap replications. They clustered host specifically, and exhibited about 16.9% diversity at the level of nucleotide sequence among Cameroonian SIVmnd strains. These results indicate that the SIVmnds isolated in Cameroon are a novel type of SIVmnd and have infected Cameroonian mandrills for a long time. We therefore designated the Cameroonian SIVmnd as SIVmnd type 2 and redesignated SIVmndGB1 as SIVmnd type 1. To date, M. sphinx is the only primate species other than humans that is naturally infected with two different types of SIV.

We investigated the effects of 6 weeks of immobilization on firing rate modulation in motor units in the first dorsal interosseous (FDI) of human volunteers. The middle finger, index finger and thumb were immobilized for a period of 6 weeks in a fibre-glass cast, which kept FDI in a shortened position. During isometric contraction at 20, 40, 60 and 80 % of maximal voluntary contraction (MVC) (index finger abduction), motor unit action potentials were recorded from the FDI using a tungsten microelectrode, and the relationship between voluntary force and mean firing rate (MFR) was obtained by plotting the MFR of each motor unit action potential train as a function of voluntary force. Four recording sessions were held for each subject: before immobilization, after 3 and 6 weeks of immobilization, and after a 6 week recovery period. As a result of immobilization, FDI volume (as measured by computerized tomography (CT) scanning) decreased, with an accompanying reduction in aggregate EMG activity per day (P < 0.01). The force measured during MVC also decreased (P < 0.05). The slope of the relationship between voluntary force and MFR was significantly decreased after immobilization, as was the range of firing rate modulation (P < 0.01). Maximal MFR, estimated from the relationship between voluntary force and MFR, was decreased (P < 0.05). MFR was also plotted against voluntary force without being normalized with respect to MVC, and the slope of the regression line was decreased (P < 0.05). Voluntary force when the MFR was 15 Hz was estimated from regression equations for the absolute force-MFR relationship, and it was increased after immobilization (P < 0.05). These results suggest that firing rate modulation shows two different adaptations to joint immobilization: a restriction of motoneurone firing to the lower rates and an enhancement of the voluntary force exerted when the MFR is relatively low.

The effects of joint immobilization on the contractile properties of human skeletal muscle were examined using the first dorsal interosseous (FDI) muscle. The middle finger, index finger and thumb were immobilized for a period of 6 weeks, and the contractile properties of FDI were tested before immobilization, after 3 and 6 weeks of immobilization, and after a 6 week recovery period. Twitch and tetanic contractions of FDI were evoked by per-cutaneous electrical stimulation. The peak twitch tension (Pt), contraction time (CT) and half-relaxation time (1/2RT) were measured from twitch contractions, while the stimulus frequency-force relationship was obtained from the tetanic contractions (2 s) evoked using various frequencies of stimulation (10-100 Hz). The fatigability of FDI was tested using Burke's fatigue protocol. Pt was significantly increased after 6 weeks of immobilization (P < 0.05) but little alteration was observed in CT or 1/2RT. No change was noted in the FDI fatigue index throughout the immobilization period. The stimulus frequency-force relationship was shifted to the left by immobilization, indicating that a larger percentage of maximal force was evoked by the lower rates of stimulation. Indeed, the tetanic force evoked by a stimulus frequency of 10 Hz was enhanced after immobilization (P < 0.05). On the other hand, the force evoked by frequencies above 50 Hz, including maximal tetanic tension, was decreased (P < 0.05). As a result, the twitch/tetanus ratio was increased (P < 0.01) after immobilization. The changes induced by immobilization in the FDI twitch/tetanus ratio and the estimated maximal firing rate of FDI motoneurones showed a significant correlation (r = 0.80, P < 0.05). It is suggested that the changes in the contractile properties of the FDI muscle seen after joint immobilization are causally linked to the changes in firing rate modulation of FDI motoneurones. There is general agreement that the properties of skeletal muscle and those of the motoneuronal system correspond well with each other in many ways; for example, muscle units with a shorter contraction time are generally governed by motoneurones with a faster conduction velocity (Burke, 1967), a higher recruitment threshold (Henneman, 1957) and a shorter duration of after-hyperpolarization (Bakels & Kernell, 1993). Furthermore, the synaptic input to motoneurones is also known to correlate well with the properties of the motoneurones and muscle (Heckman, 1994). Long-term immobilization of a joint is known to modify such properties of skeletal muscle as morphology (Tabary et al. 1972), the proportion of fast and slow muscle fibres (Tomanek & Lund, 1974) and contractility (Fischbach & Robbins, 1969; Duchateau & Hainaut, 1987). Several reports have also suggested that immobilization affects such features of the neural system controlling muscular force as the intrinsic properties of the motoneurones (Gallego et al. 1979a), the inputs to motoneurones from peripheral afferents (Gallego et al. 1979b; Manabe et al. 1989) and the descending system to motoneurones (Zanette et al. 1997). Furthermore, electromyographic (EMG) activity has also been reported to be influenced by joint immobilization (Fudema et al. 1961; Hnik et al. 1985), while Fischbach & Robbins (1969) found that aggregate EMG activity, as well as the pattern of EMG bursts, was modified after immobilization in association with changes in the contractile properties of skeletal muscle. Since EMG activity is regulated by modulating motoneuronal activity, it seemed reasonable to assume that motoneuronal activity during voluntary contractions in humans (Milner-Brown et al. 1973; Monster & Chan, 1977) would also be affected by immobilization. However, there is little evidence to indicate the existence of any correlation between joint immobilization-induced changes in motoneuronal activity and the associated changes in the contractile properties of the muscle. In the preceding paper (Seki et al. 2001) on the effects of joint immobilization on the firing properties of human motoneurones during voluntary isometric contractions of the first dorsal interosseous (FDI), we suggested that there might be two kinds of adaptation to joint immobilization: a restriction of motoneurone firing to the lower rates and an enhancement of the voluntary force exerted at low firing rates. To examine how these changes in motoneuronal activity might correlate with any changes in the contractile properties of the FDI muscle, we investigated the effect of a 6 week joint immobilization on the contractile properties of FDI. Preliminary results have been reported in abstract form (Seki et al. 1997).

The effects of practice on bilateral and unilateral reaction times (RTs) for thumb flexion tasks were investigated. Four female and 23 male students were divided into 4 groups who practiced a task under a single condition: unilateral (with either the right or left hand), bilateral, or control. Unilateral and bilateral groups practiced 20 trials 3 days a week for 6 weeks. For the left hand, the RT shortened following practice in the Unilateral-left and Bilateral groups; however, the interaction of the practice group by task was not significant. For the right hand, the RT shortened following practice, but neither the interactions of the practice group by task nor the practice group by measurement time were significant. The changes in the bilateral RTs with practice were significantly correlated with the change of the unilateral-left RT but were not significantly correlated with the change of the unilateral-right RT. As a result, no significant change in bilateral deficit was found. There was no lateral specificity in the effect of practice on RT.

Maximal voluntary strength of simultaneous bilateral exertion is known to be small compared to the sum of the unilateral exertions. This phenomenon is called bilateral deficit and the purpose of this study was to investigate whether it operates in both upper and lower limbs. A group of 7 female and 32 male students were divided into 4 training groups and a control group. The unilateral arm or leg training group performed maximal isokinetic arm or leg extensions using each arm or leg unilaterally. The bilateral arm or leg training group trained using bilateral extensions of both arms or legs. The groups in training continued these two types of resistance exercise 3 days a week, for 6 weeks. The control subjects did not train. The improvement in power brought about by training was compared from the viewpoint of whether the limbs (arms or legs) were trained or not and whether the mode of test power exertion (bilateral or unilateral) was the same as performed during training or not. The power in the trained limbs using the same regime as that during training (3.0% after 3 weeks, 7.7% after 6 weeks) showed the largest improvement ratio. This agrees with the specificity, theory in resistance training. The increase in power in untrained limbs using the same regime as during training (2.1% after 3 weeks, 3.5% after 6 weeks; P < 0.01) and the increase in power in the untrained limbs after the opposing mode of training (1.2% after 3 weeks, 2.2% after 6 weeks; P < 0.05) were larger than that of the controls (-2.5% after 3 weeks, -1.1% after 6 weeks). This suggests that the effect of resistance training was transferred to the untrained limbs (i.e. to the legs in the arm training group and to the arms in the leg training group). The degree of bilateral deficit (bilateral index, BI) in the trained limbs of the bilateral training group was shifted in a positive direction (4.2% after 3 weeks, 3.7% after 6 weeks) and that in the trained limbs of unilateral training group was shifted in a negative direction (-3.0% after 3 weeks, -5.4% after 6 weeks) by 6 weeks of training. The BI in the untrained limbs of the unilateral training group was shifted in a negative direction (-1.9% after 3 weeks, -4.5% after 6 weeks) by 6 weeks of training, whereas that in the untrained limbs of the bilateral training group was not shifted in a positive direction (-0.1% after 3 weeks, -2.4% after 6 weeks). These results would suggest that bilateral deficits in the upper and lower limbs are at least partially affected by some common mechanism at a supraspinal level.

Amiodarone-induced pulmonary toxicity is a critical and potentially fatal side effect of amiodarone. Our study was designed to reveal its clinical features, including KL-6, as an interstitial marker. The medical records of eight patients (five men and three women) with amiodarone-induced pulmonary toxicity, who had been referred to our hospital, were examined. The mean age at the initiation of amiodarone was 48 years (range, 54-87 years) and mean duration of medication prior to the development of pulmonary toxicity was 18 months (range, 7-33 months). Serum KL-6 was elevated in six of the eight patients with a range of 525-2915 U/mL. Chest computed tomography (CT) findings showed non-segmental consolidation and/or ground glass opacity. Foamy macrophages were found in bronchoalveolar lavage (BAL) fluids of all examined patients and in transbronchial lung biopsy (TBLB) specimens in half of the examined patients. We concluded that serum KL-6, chest CT findings, and foamy macrophages in BAL fluids and TBLB specimens will be helpful for the diagnosis of amiodarone-induced pulmonary toxicity.

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Adult T-cell leukemia (ATL) is a highly aggressive neoplasm of helper T lymphocytes and is etiologically associated with human T-cell leukemia virus type I (HTLV-I). Although HTLV-I encoded Tax protein is thought to play a central role in the leukemogenesis of ATL, ATL cells frequently could not produce Tax protein by the somatic mutations, deletion and loss of 5′-LTR. Moreover, a long-term latent period (almost 60 years in Japan) precedes the onset of ATL, suggesting that multistep tumorigenesis is involved in development of ATL in addition to role of viral protein. Such transformation process is thought to include alterations of host genome: genetic and epigenetic changes. The epigenetic alteration, such as DNA methylation and histone modification, is commonly observed in various cancer cells. Recently, we reported that the aberrant expression of MEL1S gene, which is hypomethylated in ATL cells, confers resistance against transforming growth factor-beta. In this study, we identified 53 aberrantly hypermethylated DNA sequences in ATL cells using methylated CpG island amplification/representational difference analysis (MCA/RDA) method. In addition, we found that the DNA methylation of these regions tends to accumulate with disease progression. Seven genes, which were expressed in normal T-cells, but suppressed in ATL cells, were identified near the hypermethylated regions. Among these silenced genes, Kruppel-like factor 4 (KLF4) gene is a cell cycle regulator and early growth response 3 (EGR3) gene is a critical transcriptional factor for induction of Fas ligand (FasL) expression. Treatment with 5-aza-2′-deoxycytidine resulted in the recovery of their transcription, indicating that their silencing is associated with DNA hypermethylation. To study their role in oncogenesis of ATL, we transfected recombinant adenovirus vectors expressing KLF4 and EGR3 genes into ATL cell lines. Expression of KLF4 induced apoptosis of ATL cells whereas enforced expression of EGR3 induced the expression of FasL gene, resulting in apoptosis. This EGR3-induced apoptosis has been inhibited by stable transfection of cellular and viral FLIP, which suppress the activation of caspase-8 by preventing pro-caspase-8 in Fas-mediated apoptosis pathway. Therefore, suppressed expression of EGR3 enabled ATL cells to escape from activation-induced cell death mediated by Fas-FasL signaling. Our results showed that the DNA hypermethylation plays an important role in the leukemogenesis of ATL by silencing transcriptions of genes that inhibit the abnormal growth of ATL cells.